A kind of preparation method of salbutamol sulfate solution

Abstract

The invention provides a preparation method of salbutamol sulfate solution, which specifically relates to the field of medicine; S1, liquid preparation: 89-91kg water for injection is added to a liquid preparation tank, the temperature of the water for injection is reduced to less than 20°C, and inert gas is continuously blown in, after the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, inert gas is continuously blown in, 885-895g of sodium chloride is added, stirred and dissolved, pH is adjusted to 3.0-4.0, 60g of salbutamol sulfate is added, stirred and dissolved, and water for injection less than 20°C is added to make the volume to 100kg to obtain liquid medicine. S2, filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain a filtrate. S3, potting: the filtrate of step S2 is potted in an ampoule bottle to obtain a finished product; S4, sterilization: the finished product is sterilized at 121°C for 12min; S5, light inspection and leak detection: the finished product is subjected to light inspection and leak detection after sterilization, and the qualified finished product is packaged, inspected and put into storage. The invention effectively solves the problem that the hardness of tablets increases after tableting, which leads to a decrease in dissolution rate.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a method for preparing a salbutamol sulfate solution. Background Art

[0002] Salbutamol sulfate is a short-acting β2 adrenergic receptor agonist that can effectively inhibit the release of allergenic substances such as histamine and prevent bronchospasm. It is the drug of choice for acute asthma attacks. Salbutamol sulfate inhalation solution and salbutamol sulfate injection are two liquid dosage forms that have the advantage of rapid onset and are widely used in clinical practice. Salbutamol sulfate is prone to degradation reactions in aqueous solutions to produce impurities due to the presence of multiple hydroxyl groups in its molecular structure. Especially after wet heat sterilization, it is affected by metal ions and the impurity level increases significantly.

[0003] Patent 201610310723.0 discloses a salbutamol sulfate solution composition for inhalation and its preparation method. The preparation method can achieve the advantages of low content of related substances, good storage stability, and suitability for industrial production, and can withstand 121°C for 15 minutes of sterilization, but the prescription contains a metal complexing agent, disodium edetate, which increases the risk of clinical medication. Patent 201810983772.X discloses a salbutamol sulfate atomized inhalation solution and its preparation method. By adding sodium gluconate as a stabilizer, the use of complexing agents is avoided, but the sterilization temperature is 60-80°C, and the sterility assurance level is low. Patent 201710078884.6 discloses a salbutamol sulfate solution for inhalation and its preparation method. The prescription is simple and can be sterilized at high temperature, but its impurity level is not disclosed. Patent 201610105354.1 discloses a method for preparing a salbutamol sulfate nebulized inhalation solution. This method is sterile throughout the process, which not only has high requirements for the production environment and equipment, but also has a sterility assurance level far lower than moist heat sterilization. Patent 202020882787.4 discloses a method for preparing a salbutamol sulfate solution. The finished product prepared by this method has a low content of related substances, good storage stability, does not contain metal chelating agents, and can withstand sterilization at 121°C for 15 minutes. However, this method requires the use of a disposable production system of low-density polyethylene, which has high production costs. Summary of the invention

[0004] In view of the above-mentioned shortcomings, the object of the present invention is to provide a method for preparing a salbutamol sulfate solution, which has a low impurity content and good stability after wet heat sterilization.

[0005] The present invention provides the following technical solutions:

[0006] A preparation method of salbutamol sulfate solution, the steps are as follows:

[0007] S1. Preparation of drug solution

[0008] Add 89-91 kg of water for injection into the liquid preparation tank, reduce the temperature of the water for injection to less than 20°C, and continue to bubble in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to bubble in inert gas, add 885-895 g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60 g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20°C to make up to 100 kg, and obtain a medicinal solution.

[0009] S2. Filtering

[0010] The drug solution passes through a stainless steel pipe and is filtered through two 0.22 μm capsule filters to obtain a filtrate.

[0011] S3. Potting

[0012] The filtrate in step S2 is filled into an ampoule bottle to obtain a finished product.

[0013] S4. Sterilization

[0014] Sterilize the finished product at 121°C for 12 minutes;

[0015] S5, Light inspection, leak detection

[0016] After sterilization, the finished products are inspected for leaks and qualified finished products are packaged, inspected and stored.

[0017] Preferably, the temperature of the liquid is kept below 25°C during potting, and the residual oxygen in the headspace is controlled to be less than 3%.

[0018] Preferably, the filling process requires that the empty ampoule be filled with nitrogen using an inert gas in advance, and after the drug solution is injected into the ampoule, the inert gas is then filled above the drug solution and then sealed.

[0019] Preferably, the inert gas can be selected from nitrogen, argon and carbon dioxide.

[0020] Preferred inert gases are nitrogen and argon.

[0021] Preferably, the nitrogen is filtered and has a purity greater than 99.99%.

[0022] Preferably, the dissolved oxygen in the liquid medicine is less than 2 mg / L and the temperature is less than 20°C.

[0023] Preferably, the equipment is made of stainless steel.

[0024] Beneficial effects of the present invention:

[0025] The present invention overcomes the defects of the prior art, saves costs and reduces the impurity level of a salbutamol sulfate solution dosage form after sterilization. The present invention reduces the temperature of the drug solution through the liquid preparation and potting process, and simultaneously fills inert gas, thereby greatly reducing the influence of metal ions in the production components and reducing the level of impurities in the finished product of the salbutamol sulfate solution preparation after sterilization; and finally obtains a salbutamol sulfate solution preparation (inhalation solution / injection) with low impurity level, high stability, quality that meets current regulatory requirements and is superior to a reference preparation. DETAILED DESCRIPTION

[0026] Example 1

[0027] S1. Preparation of liquid medicine: Add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, control the dissolved oxygen in the water for injection to be less than or equal to 2ppm, add 890g of sodium chloride, stir and dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir and dissolve, add water for injection less than 20℃ to make up to 100kg, and obtain liquid medicine, and the temperature is less than 20℃; S2. Filtration: The liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain a filtrate. S3. Filling: Fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25℃, and after the liquid medicine is injected into the ampoule bottle, it is melt-sealed; S4. Sterilization: Sterilize the finished product at 121℃ for 12min; S5. Light inspection and leak detection: After sterilization, the finished product is light inspected and leak-checked, and the qualified finished product is packaged, inspected, and put into storage. The above processes all use glass containers.

[0028] Example 2

[0029] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected and stored. The above processes all use glass containers.

[0030] Example 3

[0031] S1. Preparation of drug solution: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, control the dissolved oxygen in the water for injection to be less than or equal to 2ppm, add 890g of sodium chloride, stir and dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir and dissolve, add water for injection at less than 20℃ to make up to 100kg, and obtain the drug solution, and the temperature is less than 20℃; S2. Filtration: the drug solution passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule to obtain the finished product. The temperature of the drug solution is kept below 25℃ during filling; after injecting the drug solution into the ampoule, it is then melt-sealed; S4. Sterilization: sterilize the finished product at 121℃ for 12min; S5. Light inspection and leak detection: after sterilization, the finished product is light inspected and leak-checked, and the qualified finished products are packaged, inspected, and put into storage. The above processes all use stainless steel containers

[0032] Example 4

[0033] S1. Preparation of drug solution: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make up to 100kg, and obtain drug solution. The dissolved oxygen in the drug solution is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: The drug solution passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Potting:

[0034] Fill the filtrate of step S2 into the ampoule to obtain the finished product. During filling, the temperature of the drug solution is maintained below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%; before filling, the empty ampoule needs to be filled with nitrogen using an inert gas. After the drug solution is injected into the ampoule, the inert gas is again filled above the drug solution and then sealed; the inert gas is nitrogen, argon or carbon dioxide; the nitrogen used must be filtered and have a purity greater than 99.99%; S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished products are packaged, inspected and put into storage; the above processes all use 316L stainless steel containers;

[0035] Example 2A

[0036] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected and stored. The above processes all use glass containers, and the liquid preparation temperature is 30°C.

[0037] Example 5

[0038] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected, and stored. The sample is prepared using 316L stainless steel equipment, and the temperature of the prepared liquid medicine is maintained at 40°C for 8 hours.

[0039] Example 6

[0040] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected, and stored. The sample is prepared using 316L stainless steel equipment, and the temperature of the prepared liquid medicine is maintained at 40°C for 8 hours.

[0041] Example 7

[0042] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected, and stored. The sample is prepared using 316L stainless steel equipment, and the temperature of the prepared liquid medicine is maintained at 20°C for 8 hours.

[0043] Example 8

[0044] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected, and stored. The sample is prepared using 316L stainless steel equipment, and the temperature of the prepared liquid medicine is maintained at 10°C for 8 hours.

[0045] Example 9

[0046] S1. Preparation of liquid medicine: add 90kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to below 20℃, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2ppm, continue to blow in inert gas, add 890g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20℃ to make the volume to 100kg, and obtain liquid medicine. The dissolved oxygen in the liquid medicine is less than 2mg / L, and the temperature is less than 20℃; the inert gas is nitrogen, argon or carbon dioxide; the selected nitrogen must be filtered and the purity is greater than 99.99%; S2. Filtration: the liquid medicine passes through a stainless steel pipe and is filtered through 2 0.22μm capsule filters to obtain the filtrate. S3. Filling: fill the filtrate of step S2 into an ampoule bottle to obtain the finished product. During filling, the temperature of the liquid medicine is kept below 25°C, and the residual oxygen in the headspace is controlled to be less than 3%. Before filling, the empty ampoule bottle must be filled with nitrogen using inert gas. After the liquid medicine is injected into the ampoule bottle, the inert gas is filled above the liquid medicine, and then the ampoule bottle is sealed. The inert gas is nitrogen, argon or carbon dioxide. The nitrogen gas selected must be filtered and the purity must be greater than 99.99%. S4, sterilization: sterilize the finished product at 121°C for 12 minutes; S5, light inspection and leak detection: after sterilization, the finished product is subjected to light inspection and leak detection, and the qualified finished product is packaged, inspected, and stored. The sample is prepared using 316L stainless steel equipment, and the temperature of the prepared liquid medicine is maintained at 5°C for 8 hours.

[0047] Experimental data:

[0048] Relationship between inert gas, metal migration and product quality

[0049] The temperature of the liquid preparation process in Examples 1-4 was 30±2°C. The samples obtained from the test were numbered as Samples 1-4, respectively, and sealed in 1ml borosilicate glass ampoules and sterilized by wet heat at 121°C / 12min. The specific results are shown in the following table:

[0050]

[0051] From the above results, it can be seen that the impurity level when using 316L stainless steel preparation equipment is significantly higher than that when using glass instruments, especially impurity 1, which is greatly affected by the material. Filling with inert gas can reduce the level of related substances in the finished product. Impurities 1 and 2 have both decreased, but the decrease in impurity 1 is limited.

[0052] Relationship between preparation temperature and product quality

[0053] Example 2A: A glass container was used to prepare the sample. Inert gas was filled in both the preparation and filling processes. The dissolved oxygen in the preparation process was controlled not to exceed 2 ppm. The residual oxygen in the headspace during the filling process was controlled not to exceed 3%. The preparation temperature was 30°C.

[0054] Example 5: The sample was prepared using 316L stainless steel equipment. Inert gas was filled during the preparation and potting processes. The dissolved oxygen in the preparation process was controlled not to exceed 2ppm, and the residual oxygen in the headspace during the potting process was controlled not to exceed 3%. The temperature of the prepared drug solution was maintained at 40°C for 8h.

[0055] Example 6: The same method as in Example 5 was used to prepare a drug solution at a temperature of 30°C for 8 hours.

[0056] Example 7: The same method as in Example 5 was used to prepare a drug solution at a temperature of 20°C for 8 hours.

[0057] Example 8: The same method as in Example 5 was used to prepare a drug solution at a temperature of 10°C for 8 hours.

[0058] Example 9: The same method as in Example 5 was used to prepare a drug solution at a temperature of 5°C for 8 hours.

[0059] The obtained drug solution was sealed in a 1 ml borosilicate glass ampoule and sterilized by wet heat sterilization at 121°C / 12 min. The samples were numbered 2A, 5-9. The specific results are shown in the table below:

[0060]

[0061] From the above results, it can be seen that when using 316L stainless steel preparation equipment and filling with inert gas, the levels of related substances, especially the level of impurity 1, show an obvious linear relationship with the preparation temperature. When the preparation temperature is reduced to below 20°C, the impurity level is significantly reduced, and is close to the level of related substances when using glass containers for preparation.

[0062] Stability inspection of products under harsh conditions

[0063] Reference substance 1: Purchased imported drugs (injections) were placed under harsh conditions of 60°C, and samples were taken at 0, 10 and 30 days to test properties, pH value, related substances and content.

[0064] Sample 2A prepared in Example 2A was placed under harsh conditions at 60° C., and samples were taken at 0 days, 10 days, and 30 days to detect properties, pH value, related substances, and contents.

[0065] Sample 8 prepared in Example 8 was placed under harsh conditions at 60°C, and samples were taken at 0 days, 10 days, and 30 days to test properties, pH value, related substances and contents. Specific data are shown in the following table:

[0066]

[0067]

[0068] As can be seen from the table above, under the preparation conditions of low temperature and inert gas filling, the samples prepared with 316L stainless steel equipment can have the same quality attributes as the samples prepared with glass instruments in harsh conditions testing.

[0069] Long-term and accelerated product testing

[0070] Reference substance 2: Purchased imported drugs (injections) were placed at 25°C (long-term conditions) and 40°C (accelerated conditions), and the properties, pH value, related substances and content were tested at 0 and 3 months.

[0071] Sample 2A prepared in Example 2A was placed at 25°C (long-term condition) and 40°C (accelerated condition) respectively, and its properties, pH value, related substances and contents were tested at 0 and 3 months.

[0072] Sample 8 prepared in Example 8 was placed at 25°C (long-term condition) and 40°C (accelerated condition) respectively, and the properties, pH value, related substances and contents were tested at 0 and 3 months. The specific data are as follows:

[0073]

[0074]

[0075] As can be seen from the table above, under the preparation conditions of low temperature and inert gas filling, the samples prepared with 316L stainless steel equipment are tested at 25°C (long-term conditions) and 40°C (accelerated conditions). The samples have good stability and are comparable to the quality attributes of samples prepared using glass instruments.

[0076] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a salbutamol sulfate solution, characterized in that: Here are the steps: S1. Preparation of drug solution Add 89-91 kg of water for injection into the liquid preparation tank, lower the temperature of the water for injection to less than 20°C, and continue to blow in inert gas. After the dissolved oxygen in the water for injection is controlled to be less than or equal to 2 ppm, continue to blow in inert gas, add 885-895 g of sodium chloride, stir to dissolve, adjust the pH to 3.0-4.0, add 60 g of salbutamol sulfate, stir to dissolve, add water for injection at less than 20°C to make the volume to 100 kg, and obtain a drug solution; S2. Filtering The drug solution passed through a stainless steel pipe and was filtered through two 0.22 μm capsule filters to obtain the filtrate; S3. Potting Filling the filtrate in step S2 into an ampoule bottle to obtain a finished product; S4. Sterilization Sterilize the finished product at 121°C for 12 minutes; S5, Light inspection, leak detection After sterilization, the finished products are inspected by light and leak detection, and qualified finished products are packaged, tested and put into storage.

2. The method for preparing a salbutamol sulfate solution according to claim 1, wherein: During filling, the temperature of the drug solution was kept below 25°C and the residual oxygen in the headspace was controlled to be less than 3%.

3. The method for preparing a salbutamol sulfate solution according to claim 2, characterized in that: Before filling, the empty ampoule needs to be filled with nitrogen using inert gas. After the drug solution is injected into the ampoule, inert gas is filled above the drug solution and then sealed.

4. The method for preparing a salbutamol sulfate solution according to claim 3, wherein: The inert gas may be selected from nitrogen, argon, and carbon dioxide.

5. The method for preparing a salbutamol sulfate solution according to claim 4, characterized in that: Inert gases: nitrogen and argon.

6. A method for preparing a salbutamol sulfate solution according to claim 5, characterized in that: Nitrogen must be filtered and have a purity greater than 99.99%.

7. The method for preparing a salbutamol sulfate solution according to claim 1, characterized in that: The dissolved oxygen in the liquid medicine is less than 2 mg / L and the temperature is less than 20°C.

8. The method for preparing a salbutamol sulfate solution according to claim 1, characterized in that: The containers involved in the preparation process are made of stainless steel.

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